Abstract
N-nitrosodimethylamine (NDMA) is classified as a human carcinogen and could be produced by both natural and industrial processes. Although its toxicity and histopathology have been well-studied in animal species, there is insufficient data on the blood and tissue exposures that can be correlated with the toxicity of NDMA. The purpose of this study was to evaluate gender-specific pharmacokinetics/toxicokinetics (PKs/TKs), tissue distribution, and excretion after the oral administration of three different doses of NDMA in rats using a physiologically-based pharmacokinetic (PBPK) model. The major target tissues for developing the PBPK model and evaluating dose metrics of NDMA included blood, gastrointestinal (GI) tract, liver, kidney, lung, heart, and brain. The predictive performance of the model was validated using sensitivity analysis, (average) fold error, and visual inspection of observations versus predictions. Then, a Monte Carlo simulation was performed to describe the magnitudes of inter-individual variability and uncertainty of the single model predictions. The developed PBPK model was applied for the exposure simulation of daily oral NDMA to estimate blood concentration ranges affecting health effects following acute-duration (≤ 14 days), intermediate-duration (15–364 days), and chronic-duration (≥ 365 days) intakes. The results of the study could be used as a scientific basis for interpreting the correlation between in vivo exposures and toxicological effects of NDMA.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data generated or analysed during this study are included in this published article and its supplementary information files.
References
Allen BC, Covington TR, Clewell HJ (1996) Investigation of the impact of pharmacokinetic variability and uncertainty on risks predicted with a pharmacokinetic model for chloroform. Toxicology 111(1–3):289–303. https://doi.org/10.1016/0300-483X(96)03383-5
Anderson LM (1988) Increased numbers of N-nitrosodimethylamine-initiated lung tumors in mice by chronic co-administration of ethanol. Carcinogenesis. https://doi.org/10.1093/carcin/9.9.1717
Anderson LM, Carter JP, Logsdon DL et al (1992) Characterization of ethanol’s enhancement of tumorigenesis by N-nitrosodimethylamine in mice. Carcinogenesis. https://doi.org/10.1093/carcin/13.11.2107
Annola K, Heikkinen AT, Partanen H et al (2009) Transplacental transfer of nitrosodimethylamine in perfused human placenta. Placenta 30:277–283. https://doi.org/10.1016/j.placenta.2008.12.012
Agency for Toxic Substances and Disease Registry (ATSDR) (2023) Toxicological profile for N-nitrosodimethylamine (NDMA). https://www.atsdr.cdc.gov/toxprofiles/tp141.pdf
Buur J, Baynes R, Smith G, Riviere J (2006) Use of probabilistic modeling within a physiologically based pharmacokinetic model to predict sulfamethazine residue withdrawal times in edible tissues in swine. Antimicrob Agents Chemother. https://doi.org/10.1128/AAC.01355-05
Cai L, Ke M, Wang H et al (2023) Physiologically based pharmacokinetic model combined with reverse dose method to study the nephrotoxic tolerance dose of tacrolimus. Arch Toxicol 97(10):2659–2673. https://doi.org/10.1007/s00204-023-03576-3
Chetty M, Johnson TN, Polak S et al (2018) Physiologically based pharmacokinetic modelling to guide drug delivery in older people. Adv Drug Deliv Rev 135:85–96. https://doi.org/10.1016/J.ADDR.2018.08.013
Chiu WA, Barton HA, DeWoskin RS et al (2007) Evaluation of physiologically based pharmacokinetic models for use in risk assessment. J Appl Toxicol 27(3):218–237. https://doi.org/10.1002/jat.1225
Clewell RA, Clewell HJ (2008) Development and specification of physiologically based pharmacokinetic models for use in risk assessment. Regul Toxicol Pharmacol 50:129–143. https://doi.org/10.1016/j.yrtph.2007.10.012
Eisenblaetter T, Teichert L, Burnette R, Hutson P (2020) Dose linearity and proportionality. In: Drug discovery and evaluation: methods in clinical pharmacology, 2nd edn. Springer International Publishing, pp 695–714. https://doi.org/10.1007/978-3-319-68864-0_5
EMA (2018) Guideline on the reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation. European Medicines Agency, EMA/CHMP/458101/2016. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-reporting-physiologically-based-pharmacokinetic-pbpk-modelling-and-simulation_en.pdf
Emond C, Multigner L (2022) Chlordecone: development of a physiologically based pharmacokinetic tool to support human health risks assessments. Arch Toxicol. https://doi.org/10.1007/s00204-022-03231-3
Espié P, Tytgat D, Sargentini-Maier ML et al (2009) Physiologically based pharmacokinetics (PBPK). Drug Metab Rev 41(3):391–407. https://doi.org/10.1080/10837450902891360
Fo A, En M, Maduagwu EN (2004) Pharmacokinetics of biliary excretion of N-nitrosodi-methylamine in rats fed diets containing levels of protein. Malawi Med J 16(1):6–8
Freund HA (1937) Clinical manifestations and studies in parenchymatous hepatitis. Ann Intern Med 10:1144–1155
George B, Lumen A, Nguyen C et al (2020) Application of physiologically based pharmacokinetic modeling for sertraline dosing recommendations in pregnancy. NPJ Syst Biol Appl 6:36. https://doi.org/10.1038/s41540-020-00157-3
George J, Tsuchishima M, Tsutsumi M (2019) Molecular mechanisms in the pathogenesis of N-nitrosodimethylamine induced hepatic fibrosis. Cell Death Dis 10:18. https://doi.org/10.1038/s41419-018-1272-8
Gombar CT, Pylypiw HM, Harrington GW (1987) Pharmacokinetics of N-nitrosodimethylamine in Beagles. Cancer Res 47(2):343–347
Gombar CT, Harrington GW, Pylypiw HM, et al (1988) Pharmacokinetics of N-nitrosodimethylamine in swine. Carcinogenesis 9(8):1351–1354. https://doi.org/10.1093/carcin/9.8.1351
Grandoni S, Cesari N, Brogin G et al (2019) Building in-house PBPK modelling tools for oral drug administration from literature information. ADMET DMPK. https://doi.org/10.5599/admet.638
Graves RJ, Swann PF (1993) Clearance of N-nitrosodimethylamine and N-nitrosodiethylamine by the perfused rat liver: relationship to the Km, and Vmax for nitrosamine metabolism. Biochem Pharmacol 45:983–989
Henri J, Carrez R, Méda B et al (2017) A physiologically based pharmacokinetic model for chickens exposed to feed supplemented with monensin during their lifetime. J Vet Pharmacol Ther 40:370–382. https://doi.org/10.1111/jvp.12370
Hidajat M, McElvenny DM, Ritchie P et al (2019) Lifetime exposure to rubber dusts, fumes and N-nitrosamines and cancer mortality in a cohort of British rubber workers with 49 years follow-up. Occup Environ Med. https://doi.org/10.1136/oemed-2018-105181
Hinuma K, Matsuda J, Tanida N et al (1990) N-nitrosamines in the stomach with special reference to in vitro formation, and kinetics after intragastric or intravenous administration in rats. Gastroenterol Jpn. https://doi.org/10.1007/BF02779329
Jakszyn P, Agudo A, Berenguer A et al (2006) Intake and food sources of nitrites and N-nitrosodimethylamine in Spain. Public Health Nutr 9:785–791. https://doi.org/10.1079/phn2005884
Kang DW, Kim KM, Kim JH, Cho HY (2023) Application of minimal physiologically-based pharmacokinetic model to simulate lung and trachea exposure of pyronaridine and artesunate in hamsters. Pharmaceutics. https://doi.org/10.3390/pharmaceutics15030838
Khalil F, Läer S (2011) Physiologically based pharmacokinetic modeling: methodology, applications, and limitations with a focus on its role in pediatric drug development. J Biomed Biotechnol 2011:907461. https://doi.org/10.1155/2011/907461
Kopańska K, Rodríguez-Belenguer P, Llopis-Lorente J et al (2023) Uncertainty assessment of proarrhythmia predictions derived from multi-level in silico models. Arch Toxicol 97:2721–2740. https://doi.org/10.1007/s00204-023-03557-6
Kuepfer L, Niederalt C, Wendl T et al (2016) Applied concepts in PBPK modeling: how to build a PBPK/PD model. CPT Pharmacometr Syst Pharmacol 5:516–531
Li Z, Ridder BJ, Han X et al (2019) Assessment of an in silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.1184
Lijinsky W, Kovatch RM (1989) Carcinogenesis by nitrosamines and azoxyalkanes by different routes of administration to rats. Biomed Environ Sci 2(2):154–159
Lijinsky W, Reuber MD (1984) Carcinogenesis in rats by nitrosodimethylamine and other nitrosomethylalkylamines at low doses. Cancer Lett. https://doi.org/10.1016/0304-3835(84)90047-8
Lin JH (1994) Dose-dependent pharmacokinetics: experimental observations and theoretical considerations. Biopharm Drug Dispos 15:1–31
Liu L, Pang KS (2006) An integrated approach to model hepatic drug clearance. Eur J Pharm Sci 29:215–230. https://doi.org/10.1016/j.ejps.2006.05.007
Luecke RH, Pearce BA, Wosilait WD et al (2007) Postnatal growth considerations for PBPK modeling. J Toxicol Environ Health—Part A Curr Issues 70:1027–1037. https://doi.org/10.1080/15287390601172056
Magee PN (1956) Toxic liver injury. The metabolism of dimethylnitrosamine. Biochem J 64:676
Maharaj AR, Wu H, Hornik CP et al (2020) Use of normalized prediction distribution errors for assessing population physiologically-based pharmacokinetic model adequacy. J Pharmacokinet Pharmacodyn. https://doi.org/10.1007/s10928-020-09684-2
Mayberry KM, Bloemer J, Ray SD (2020) Drugs of abuse. Side Effects Drugs Annual 42:33–53. https://doi.org/10.1016/BS.SEDA.2020.09.004
Mehvar, Reza (2001) Principles of nonlinear pharmacokinetics. Am J Pharm Educ 65(2):178–184
Mico BA, Swagzdis JE, Hu HS-W et al (1985) Low-dose in vivo pharmacokinetic and deuterium isotope effect studies of N-nitrosodimethylamine in rats. Cancer Res 45(12 Pt 1):6280–6285
Park JE, Seo JE, Lee JY, Kwon H (2015) Distribution of seven N-nitrosamines in food. Toxicol Res 31:279–288. https://doi.org/10.5487/TR.2015.31.3.279
Pegg AE, Perry W (1981) Alkylation of nucleic acids and metabolism of small doses of dimethylnitrosamine in the rat. Cancer Res 41(8):3128–3132
Peto R, Gray R, Brantom P, Grasso P (1984) Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA alone of the effect of age of starting (3, 6 or 20 weeks) and of species (rats, mice or hamsters). IARC Sci Publ 1984(57):627–665
Peto R, Gray R, Brantom P, Grasso P (1991a) Dose and time relationships for tumor induction in the liver and esophagus of 4080 inbred rats by chronic ingestion of A-nitrosodiethylamine or W-nitrosodimethylamine. Cancer Res 51(23 Pt 2):6452–6469
Peto R, Gray R, Brantom P, Grasso P (1991b) Effects on 4080 rats of chronic ingestion of N-nitrosodiethylamine or N-nitrosodimethylamine: a detailed dose-response study. Cancer Res 51(23 Pt 2):6415–6451
Pflaum T, Hausler T, Baumung C et al (2016) Carcinogenic compounds in alcoholic beverages: an update. Arch Toxicol 90(10):2349–2367. https://doi.org/10.1007/s00204-016-1770-3
Ramboer E, Vanhaecke T, Rogiers V, Vinken M (2013) Primary hepatocyte cultures as prominent in vitro tools to study hepatic drug transporters. Drug Metab Rev 45(2):196–217. https://doi.org/10.3109/03602532.2012.756010
Shankaran H, Adeshina F, Teeguarden JG (2013) Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels. Toxicol Appl Pharmacol 273:464–476. https://doi.org/10.1016/j.taap.2013.05.024
Sterner TR, Ruark CD, Covington TR et al (2013) A physiologically based pharmacokinetic model for the oxime TMB-4: Simulation of rodent and human data. Arch Toxicol 87:661–680. https://doi.org/10.1007/s00204-012-0987-z
Streeter AJ, Nims RW, Wu PP, Logsdon DL (1990) Toxicokinetics of N-nitrosodimethylamine in the Syrian golden hamster. Arch Toxicol 64(7):562–566. https://doi.org/10.1007/BF01971835
Swann PF, Coe AM, Mace R (1984) Ethanol and dimethylnitrosamine and diethylnitrosamine metabolism and disposition in the rat possible relevance to the influence of ethanol on human cancer incidence. Carcinogenesis. https://doi.org/10.1093/carcin/5.10.1337
Tanaka C, Kawai R, Rowland M (1999) Physiologically based pharmacokinetics of cyclosporine a: reevaluation of dose-nonlinear kinetics in rats. J Pharmacokinet Biopharm 27(6):597–623. https://doi.org/10.1023/a:1020978509566
Taniguchi M, Yasutake A, Takedomi K, Inoue K (1999) Effects of N-nitrosodimethylamine (NDMA) on the oxidative status of rat liver. Arch Toxicol. https://doi.org/10.1007/s002040050598
Thiel C, Schneckener S, Krauss M et al (2015) A systematic evaluation of the use of physiologically based pharmacokinetic modeling for cross-species extrapolation. J Pharm Sci. https://doi.org/10.1002/jps.24214
Ungar H (1986) Venoocclusive disease of the liver and phlebectatic peliosis in the golden hamster exposed to dimethylnitrosamine. Pathol Res Pract. https://doi.org/10.1016/S0344-0338(86)80008-5
US EPA (2006) Approaches For the Application of Physiologically Based Pharmacokinetic (PBPK) Models and Supporting Data In Risk Assessment. U.S. Environmental Protection Agency, EPA/600/R-05/043F. https://ordspub.epa.gov/ords/eims/eimscomm.getfile?p_download_id=458188
US EPA (2007) Provisional Peer Reviewed Toxicity Values for N-Nitrosodimethylamine (CASRN 62-75-9). U.S. Environmental Protection Agency, EPA/690/R-07/024F. https://cfpub.epa.gov/ncea/pprtv/documents/NitrosodimethylamineN.pdf
US EPA (2017) Technical Fact Sheet—N-nitroso-dimethylamine (NDMA). U.S. Environmental Protection Agency, EPA 505-F-17-005. https://19january2021snapshot.epa.gov/sites/static/files/2017-10/documents/ndma_fact_sheet_update_9-15-17_508.pdf
Varga F (1976) Transit time changes with age in the gastrointestinal tract of the rat. Digestion 14:319–324
Vdoviaková K, Petrovová E, Maloveská M et al (2016) Surgical anatomy of the gastrointestinal tract and its vasculature in the laboratory rat. Gastroenterol Res Pract. https://doi.org/10.1155/2016/2632368
Yim DS, Choi S, Bae SH (2020) Predicting human pharmacokinetics from preclinical data: Absorption. Transl Clin Pharmacol 28:126–135. https://doi.org/10.12793/tcp.2020.28.e14
Yim DS (2016) Revisiting the well-stirred model of hepatic clearance: QH, CLH and F changing in the same direction. Transl Clin Pharmacol 24:115–118. https://doi.org/10.12793/tcp.2016.24.3.115
Acknowledgements
This research was supported by Daewoong Pharmaceutical Co., Ltd (Yongin, Republic of Korea).
Author information
Authors and Affiliations
Contributions
DWK: Writing—original draft, investigation, visualization. JHK: Writing—review and editing, data curation, formal analysis. GWC: Writing—review and editing. SC: validation. HYC: conceptualization, methodology, supervision.
Corresponding author
Ethics declarations
Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Kang, D.W., Kim, J.H., Choi, GW. et al. Physiologically-based pharmacokinetic model for evaluating gender-specific exposures of N-nitrosodimethylamine (NDMA). Arch Toxicol 98, 821–835 (2024). https://doi.org/10.1007/s00204-023-03652-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-023-03652-8